Pato's Populations

The search for the genetic basis of serious mental illnesses has taken Carlos Pato out of the laboratory and to a group of islands in the middle of the Atlantic Ocean.

By Lori Oliwenstein

Just before press time for USC Health, Carlos Pato, M.D., and his wife, Michele Pato, M.D., were among a group of pedestrians injured when struck by an SUV following a multiple-car accident in Pittsburgh, PA. Carlos Pato suffered a leg injury but was mobile a few days after the April 1 accident and his recovery continues. Michele Pato incurred severe trauma to the head. She was alert and responsive and making a dramatic recovery, according to family members.

The world—or, at least, a couple of its most enchanting archipelagos—is Carlos Pato’s research laboratory.

He knows that unraveling the genetics behind some of psychiatry’s most devastating illnesses will not be accomplished at a laboratory bench. To understand the genetic basis of illnesses such as schizophrenia and bipolar disorder, he says, you have to find and study the people who have these illnesses and learn how they acquire them as first steps toward devising treatments and finding cures.

He has spent his career studying the genetics of psychotic disorders. But the many different types of these diseases make the search for precise insights daunting.

Pato, M.D., is the new chair of the Department of Psychiatry and Behavioral Sciences at the Keck School of Medicine of USC. His wife and research collaborator, Michele Pato, M.D., is a professor in the department and the Keck School’s first associate dean for academic scholarship. The department has 45 faculty members and a long record of clinical service to the residents of Los Angeles County, particularly at the LAC+USC Medical Center.

Pato’s scientific interests blend well with USC’s growing strengths in epidemiology, genetics and computational biology.

Because psychiatric disorders vary widely, Pato has focused on people in the Azores and Madeiras— archipelagos that never had a native population until Portuguese settled them in the 1400s. Because their genetic history is more stable, studying their genes narrows the search for meaning.

A unique population

“You can go back 500 years… to see how new families were added to this genetic pool,” Pato says. “Basically, we’re just taking advantage of a long natural history experiment.”

Because the islands chains are a thousand miles apart, yet share an almost-identical history, researchers can compare findings in one against the other. There are about 3,500 subjects on the islands the team follows, tracking their family histories to predict who is at risk. They also try to determine how genetic risk combines with non-genetic factors to determine whether a child develops one of these illnesses, says Pato, who also holds the Franz Alexander Chair in Psychiatry at the Keck School.

The Pato study, led by both Carlos and Michele Pato, has documented nearly every case of schizophrenia and bipolar disorder on the islands, collected psychiatric assessments and blood samples. Typically, scientists study a sample of a population, not an entire population, which in this case numbers more than 250,000.

Because the people in the Azores have lived with very little contact or marriage with outsiders, they have a lot of DNA in common. That means there is less variability within the population’s genome, simplifying the search for genes related to schizophrenia and bipolar disorder.

What Pato and his colleagues have found is that a few sites on certain chromosomes appear to be linked to the development of the illnesses under evaluation. They have linked bipolar disorder to three different chromosomes, and schizophrenia to a fourth.

An American pedigree

Born in Coimbra, Portugal, Pato received a bachelor’s degree in comparative literature from Brown University and earned a medical degree from the University of Cincinnati College of Medicine in 1983. He was a research fellow at the National Institute of Mental Health in Bethesda, Md., and served as chief of the genetics research program in the Schizophrenia Research Branch.

Pato came to the Keck School from a dual role as associate chief of staff for research and development at the Veteran’s Administration Medical Center in Washington, D.C., and as a professor with the Center for NeuroPsychiatric Genetics at the State University of New York Upstate Medical University, Syracuse. He also holds a Distinguished Professorship at Georgetown University.

Pato’s research typically involves colleagues at other institutions. At Syracuse, for example, Pato’s team extracted DNA from the blood samples of patients, then, with the help of colleagues at the Whitehead Institute at MIT and the Clark Institute in Toronto, scanned all 23 chromosomes of DNA searching for links to schizophrenia, bipolar disorder and psychosis. At the time, Pato said, “Our DNA scan of patients in the Azores with schizophrenia, bipolar disorder and psychosis found 20 areas that may hold genes responsible for the disorders. And a more detailed study of one of those areas—on chromosome 5—clearly supports a correlation between genes on that chromosome and schizophrenia.”

From that point forward, the plan was to do a finer mapping—one million tests—of that region on chromosome 5 to get a clear idea of the genes involved. Today’s gene mapping technology enables researchers to perform thousands of tests at one time. If an appropriate gene is discovered, the development of treatments can begin.

In much of the world about 10 to 15 percent of patients with schizophrenia have relatives with the disease, but Pato’s team found that in the Azores the number approaches 60 percent. Many in the study did not know they had relatives who were sick, Pato says, but were found through the study. The finding supports the theory that schizophrenia is familial and genetic.

Schizophrenia strikes about 1 percent of the world’s population, but in the Azores that number is just 0.3 percent. Moreover schizophrenia and bipolar disorder are probably a collection of different disorders as well—not one, but many diseases. Because Azorean people are isolated, they have been subject to only a few variations.

Last December, working with the Broad Institute at MIT, Pato began a project to complete a map of chromosome 5’s schizophrenia link, using sophisticated techniques that are part of a global study called the International HapMap Project. At USC, a major HapMap project is underway with a $19 million grant from the National Institutes of Health to expand the ability to find disease-related genes and extract knowledge from the Human Genome Project. Headed by computational geneticist Michael Waterman, a pioneer in sequencing the human genome, it also involves researchers at the Keck School.

“Clearly, the Keck School has made a major investment in strengthening its position as a first-rate research medical school with a special focus of interest in human genetics and neuroscience,” Pato says. “That made coming here a natural for me, since I’ve been immersed in the genetics of neuropsychiatric disorders throughout my career.

“One of the most exciting new challenges will be to develop a productive, state-of-the-art neuropsychiatric genetics and epidemiology research program, focusing on how it will complement other departments and institutes at the Keck School as well as departments and schools on the University Park Campus.

“But one of the special challenges will be to see how this department can fit in with the greater medical mission of the school, to integrate psychiatry as optimally as we can with the rest of the specialties. We will be focusing both on the future of psychiatric research and on the immediate future of delivery of care of psychiatric patients. I think all of this has to be done in the context of our primary mission of education at all levels, and the really important academic development of our faculty on an ongoing basis.”

“The era of genomic psychiatry is beginning,” Pato says. “A lot of this work is very much complementary to work people at the Keck School have been pursuing in parallel areas like cancer genetics. The potential synergies are really exciting; I’ve already begun working actively with the biostatistics group in preventive medicine, and I’m looking forward to collaborating closely with them and others.”

Alfred Kildow contributed to this story.